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On-line Access: 2021-09-10

Received: 2021-01-24

Revision Accepted: 2021-04-13

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Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Nannan SUN

https://orcid.org/0000-0002-8810-0078

Zhigang FAN

https://orcid.org/0000-0002-1190-0894

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Journal of Zhejiang University SCIENCE B 2021 Vol.22 No.9 P.746-756

http://doi.org/10.1631/jzus.B2100053


Endoplasmic reticulum stress is involved in retinal injury induced by repeated transient spikes of intraocular pressure


Author(s):  Xue YANG, Xiaowei YU, Zhenni ZHAO, Yuqing HE, Jiamin ZHANG, Xiaoqian SU, Nannan SUN, Zhigang FAN

Affiliation(s):  State Key Laboratory of Ophthalmology, Department of Glaucoma, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; more

Corresponding email(s):   sun_nann@163.com, fanzhigang@mail.ccmu.edu.cn

Key Words:  Endoplasmic reticulum (ER) stress, Intraocular pressure spike (Spike IOP), Retinal injury, Neuron apoptosis, Glaucoma


Xue YANG, Xiaowei YU, Zhenni ZHAO, Yuqing HE, Jiamin ZHANG, Xiaoqian SU, Nannan SUN, Zhigang FAN. Endoplasmic reticulum stress is involved in retinal injury induced by repeated transient spikes of intraocular pressure[J]. Journal of Zhejiang University Science B, 2021, 22(9): 746-756.

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author="Xue YANG, Xiaowei YU, Zhenni ZHAO, Yuqing HE, Jiamin ZHANG, Xiaoqian SU, Nannan SUN, Zhigang FAN",
journal="Journal of Zhejiang University Science B",
volume="22",
number="9",
pages="746-756",
year="2021",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2100053"
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%0 Journal Article
%T Endoplasmic reticulum stress is involved in retinal injury induced by repeated transient spikes of intraocular pressure
%A Xue YANG
%A Xiaowei YU
%A Zhenni ZHAO
%A Yuqing HE
%A Jiamin ZHANG
%A Xiaoqian SU
%A Nannan SUN
%A Zhigang FAN
%J Journal of Zhejiang University SCIENCE B
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%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2100053

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T1 - Endoplasmic reticulum stress is involved in retinal injury induced by repeated transient spikes of intraocular pressure
A1 - Xue YANG
A1 - Xiaowei YU
A1 - Zhenni ZHAO
A1 - Yuqing HE
A1 - Jiamin ZHANG
A1 - Xiaoqian SU
A1 - Nannan SUN
A1 - Zhigang FAN
J0 - Journal of Zhejiang University Science B
VL - 22
IS - 9
SP - 746
EP - 756
%@ 1673-1581
Y1 - 2021
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2100053


Abstract: 
Clinically, a large proportion of glaucoma patients undergo repeated intraocular pressure (IOP) spike (Spike IOP) attacks during their sleep, which may facilitate retinopathy. In this study, we established a mouse model of repeated transient Spike IOP to investigate the direct damage to the retina following Spike IOP attacks, and elucidated the underlying molecular mechanism. We analyzed the changes in the number of retinal ganglion cells (RGCs) via immunofluorescence. Thereafter, we detected retinal cell apoptosis via terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining, and performed RNA sequencing (RNA-seq) to reveal the underlying molecular mechanism. Finally, we validated the expression of key molecules in the endoplasmic reticulum (ER) stress pathway using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. Results revealed a time-dependent RGC loss in Spike IOP, evidenced by a reduction in the number of Brn3a-positive RGCs in experimental eyes following a 7-d continuous treatment with Spike IOP. In addition, TUNEL staining indicated that apoptosis of retinal cells started in the outer nuclear layer (ONL), and then spread to the ganglion cell layer (GCL) with time. RNA-seq analysis revealed that ER stress might be involved in Spike IOP-induced retinal injury. This result was corroborated by western blot, which revealed upregulation of ER stress-related proteins including binding immunoglobulin protein/glucose-regulated protein 78 (BiP/GRP78), phosphorylated inositol-requiring enzyme 1 (p-IRE1), unspliced X-box-binding protein 1 (XBP1-u), spliced X-box-binding protein 1 (XBP1-s), phosphorylated c-Jun N-terminal kinase (p-JNK), C/EBP-homologous protein (CHOP), and B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax). These findings indicate that repeated IOP transients are detrimental to the retina, while ER stress plays an important role in retinal cell apoptosis in this situation. Notably, repeated Spike IOP among glaucoma patients is a crucial factor for progressive retinopathy.

内质网应激参与反复瞬时高眼压诱导的视网膜损伤

目的:研究和探讨反复瞬时高眼压对视网膜的损伤作用及其潜在的分子机制。
创新点:模拟临床上青光眼患者夜间难以检测到的眼压峰值波动对视网膜的影响,首次证明反复的瞬时高眼压对视网膜具有直接损伤效应,其损伤机制与内质网应激通路激活有关。
方法:通过眼前房生理盐水灌注,建立小鼠反复瞬时高眼压模型(50mmHg,1min×7次),连续灌注处理1、3和7天后,采用视网膜铺片(Whole-mount retina)评估视网膜神经节细胞(RGC)损伤情况;用TUNEL法检测视网膜全层细胞凋亡;用转录组测序(RNA-seq)筛选参与视网膜损伤的分子通路;用实时荧光定量聚合酶链式反应(qRT-PCR)和蛋白免疫印迹(Western blot)进一步检测内质网应激通路相关分子的表达。
结论:反复瞬时高眼压可以损伤视网膜全层,并呈时间依赖性的由外核层细胞(ONL)死亡进展至视网膜神经节细胞层(GCL)死亡。内质网应激相关信号通路中肌醇酶1(IRE1)信号通路激活参与了视网膜的损伤过程。

关键词:内质网应激;瞬时眼压峰值(Spike IOP);视网膜损伤;视网膜神经细胞凋亡;青光眼

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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